Anxiety disorders are highly prevalent in the population and carry a significant burden of distress and impairment. Current treatments are limited, and, compared to other psychiatric conditions, research in anxiety disorders has been relatively neglected. Exploring their genetic determinants will help elucidate their causes and guide research for prevention and new treatments. We propose to test candidate anxiety disorder susceptibility genes selected from preliminary mouse and human data in a unique human genetic epidemiologic sample. We used multivariate structural equation modeling to identify common genetic risk factors for related phenotypes of generalized anxiety disorder, panic disorder, agoraphobia, social phobia, major depression, and neuroticism in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available is selected as a case or control based upon scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls will be entered into a two- stage association study in which candidate loci are screened in stage 1, the positive results of which are tested for replication in stage 2. This two-stage design was chosen to reduce genotyping costs and control false-discovery rates. Potential bias from population stratification will be assessed and controlled using data from a set of highly-informative anonymous markers genotyped in the entire sample. Primary data from a whole-genome association study in mouse fear-related phenotypes will be used to identify a preliminary set of candidate genomic regions. This will be integrated with other data from genome-wide linkage and association studies in human and animal anxiety phenotypes to select a smaller set of high-priority candidate genes for testing in our human sample. Haplotype-tagging and functional polymorphic SNPs, where available, will be chosen from publicly-available databases using standard algorithms to incorporate the main sources of genetic variation across these candidate gene regions. To our knowledge, this is the first application to systematically integrate information derived from primary animal studies of fear-related phenotypes with human anxiety disorder data to identify the susceptibility genes for these conditions. [unreadable] [unreadable] [unreadable] [unreadable]